Tumours of the urogenital tract

CHAPTER

17

Tumours of the urogenital tract TUMOURS OF THE FEMALE GENITAL TRACT Canine mammary tumours Mammary tumours are the second most common tumours of dogs (second to skin tumours) (Moulton 1999) (Figure 17.1). Mammary tumours are still frequently encountered in countries were ovariohysterectomy (OHE) or ovariectomy is not routinely performed on young female dogs that are not acquired for breeding purposes. A number of studies have shown that early OHE protects female dogs from developing mammary cancer in later life. The risk of developing mammary cancer if spayed prior to first heat is 0.05%, 8% after 1st, and 26% after 2nd, compared to intact dogs (Schneider et al 1969). OHE after four or more cycles or greater than 2.5 years of age has little or no protective effect on the development of malignant mammary tumours (Misdorp 1988, Schneider et al 1969). It is therefore a preventable condition and as such client counselling and veterinary surgeon awareness will continue to reduce the incidence of this preventable cancer.

Pathogenesis The correlation with protection against developing mammary tumours and OHE indicates priming of the mammary tissue under hormonal influence. Prolonged, dose-related exposure to synthetic progestins has been shown to induce proliferation of mammary epithelial cells, potentially leading to genetic errors that may subsequently result in the development of mammary tumours (benign and malignant) (Misdorp 1991, Støvring & Glattre 1997). Administration of diethylstilboestrol is associated with ovarian tumour development but not mammary (Jabara 1962a,b). The exact mechanisms and interactions at the cellular level that lead to the development of malignant mammary tumours are unknown. Hormonal therapy (anti-oestrogen drugs such as tamoxifen) has been shown to delay the onset of metastatic disease in humans with oestrogen receptor-positive tumours. The presence of oestrogen, progesterone and prolactin receptors on canine mammary tissue and tumours has been evaluated (Rutteman & Misdorp 1993). Only 50% of malignant primary tumours were positive for these receptors and they were infrequently detected on metastatic lesions. The role of dietary factors in the development of canine mammary tumours is undetermined although one study did indicate that obesity at 1 year of age may lead to an increased risk of developing mammary neoplasia (without consideration of OHE) (Pérez-Alenza et al 1998).

Clinical signs The presence of a mass associated with the mammary tissue warrants investigation. The caudal mammary glands are said to be more frequently involved than the cranial glands, and tumours can present as either isolated lumps or multiples. In the case of multiple lumps, each one must be treated as an individual. Usually, these lumps are non-painful; they may appear and remain static or grow rapidly. Cystic lesions can also be present in the mammary tissue, but care is required when evaluating such lesions as there may be underlying tumour associated with what appears cytologically to be cystic fluid.

Evaluation of the patient Signalment Most mammary tumours arise in middle-aged intact females with a peak incidence between 6 and 10 years of age (Egenvall et al 2005). Mammary cancer in males is rare (<1% of all mammary tumours occur in males) (Lana et al 2007), and female dogs are 62 times more likely to develop mammary gland tumours than male dogs (Saba et al 2007). In a recent study of eight male dogs with mammary tumours, seven out of eight tumours were benign, for which surgery alone provided long-term control (Saba et al 2007). Affected male dogs may have an oestrogen-secreting Sertoli cell tumour of the testis (Moulton 1999). Mammary neoplasia is rarely seen in young dogs (Egenvall et al 2005); however, benign cystic hyperplasia can be seen in dogs involving all mammary glands. This is typically seen in dogs during metoestrus, pregnancy or after treatment with progestins. This usually resolves without surgical intervention (Rutteman & Kirpensteijn 2003). History It is important to ascertain the reproductive status of the patient, the stage of oestrus cycle, the time the lump has been present and if it has grown since first noticed. Physical examination A good physical examination is required. The mammary lump should be palpated for size, whether fixed to underlying tissue or freely movable, any enlargement of the draining lymph nodes, and any ulceration or oedema. These findings, coupled with the client’s perception of rate of growth, are all indicators of potential malignancy. Cytology Fine needle aspiration (FNA) cytology to differentiate benign mammary adenoma from malignant carcinoma is generally

17

Tumours of the urogenital tract

Table 17.1  WHO staging of canine mammary tumours

Tumour

Regional lymph node (LN)

Distant metastasis

T0: no measurable tumour

N0: no LN metastasis

M0: no distant metastasis

T1: <3 cm

N1: LN metastasis

M1: distant metastasis

T2: 3–5 cm T3: >5 cm T4: inflammatory Ca

Figure 17.1  Large mammary gland tumour in a dog. (Courtesy S Withrow.)

unhelpful, due to mixed cell populations within mammary tumours. Biopsy Incisional biopsies give more information than cytology and may be useful to assist in staging and surgical planning; however, excisional biopsies are often more appropriate to provide diagnosis, prognosis and treatment in one step (see surgical treatment below). If an incisional biopsy is taken it is still important to submit the final specimen for evaluation by a pathologist; more than one benign biopsy has been shown to have a malignant component on final histopathology.

Staging the patient Approximately 50% of mammary tumours are benign adenomas that are curable with adequate surgery (Brodey et al 1983, Gilbertson et al 1983). A large percentage of mammary carcinomas are low grade and carry a fair prognosis with adequate excision. The prognosis for non-invasive carcinoma is very good (Kurzman & Gilbertson 1986). Aggressive carcinomas are seen less frequently but warrant a guarded prognosis (Kurzman & Gilbertson 1986). Inflammatory carcinomas warrant a very poor prognosis, with a median survival time (MST) of 25 days with palliative care (Peña et al 2003, PérezAlenza et al 2001). For a patient with suspected malignant mammary cancer, staging is important. The tumour/node/metastasis (TNM) system proposed by the World Health Organization (WHO) is typically used to stage veterinary patients with mammary tumours (Table 17.1).

1. Establish a minimum database of routine biochemistry, haematology and urinalysis. 2. Physically check the draining lymph nodes for any enlargement. If palpable, FNA of the regional lymph node should be taken and evaluated for neoplastic cells. 3. Thoracic radiographs, good quality right and left laterals are required to assess for metastatic disease. CT may be of more use for the detection of pulmonary metastatic disease from mammary gland neoplasia, as radiographs are not very sensitive, detecting metastasis in only one of six dogs with necropsy-confirmed intrathoracic metastasis (Baumann et al 2004). Furthermore, CT has 152

a: not fixed

a: not fixed

b: fixed

b: fixed

(With permission from the World Health Organization.)

Table 17.2a  Clinical staging of canine mammary tumours

Clinical stage

Tumour

Regional lymph node Metastasis

I

T1

N0

M0

II

T0, T1

N1

M0

T2

N0, N1

M0

T3

N0, N1

M0

T0–T3

N1

M0

IV

T0–T3

N0, N1

M1

V

T4

N0, N1

M1

III

After Owen (1980). (With permission from the World Health Organization.)

Table 17.2b  Histological staging of canine mammary tumours

Stage 0

Tumour cells limited to ductal tissue

I

Tumour cells invading stromal tissue

II

Vascular/lymphatic invasion, regional lymph node metastasis

III

Distal metastasis present

After Gilbertson et al (1983).

been shown to be more sensitive than radiographs for detecting pulmonary metastases (Nemanic et al 2006). Clinical and histological staging of mammary tumours are shown in Table 17.2a,b.

Poor prognostic signs • Inflammatory (Peña et al 2003, Pérez-Alenza et al 2001) • Size (<3 cm better than >3 cm) (Bostock 1986, Chang et al 2005, Kurzman & Gilbertson 1986, Philibert et al 2003) • Ulceration (Chang et al 2005, Hellmén et al 1993, PérezAlenza et al 1997) • Node positive (for stage, see Table 17.2b) (Chang et al 2005, Gilbertson et al 1983, Hellmén et al 1993,

Canine mammary tumours

•

•

• • • • • • • • • •

Karayannopoulou et al 2005, Kurzman & Gilbertson 1986, Yamagami et al 1996) Histological type and grade (Benjamin et al 1999, Chang et al 2005, Gilbertson et al 1983, Hellmén et al 1993, Karayannopoulou et al 2005, Kurzman & Gilbertson 1986, Misdorp et al 1971, Peña et al 2003, Pérez-Alenza et al 2001) Invasiveness (including fixation to underlying tissue) (Gilbertson et al 1983, Hellmén et al 1993, Kurzman & Gilbertson 1986) Presence of distant metastasis (Chang et al 2005) Degree of nuclear differentiation (Gilbertson et al 1983, Karayannopoulou et al 2005) Evidence of lymphoid cellular reactivity in tumour vicinity (Gilbertson et al 1983) Intravascular growth, steroid hormone receptor activity (Geraldes et al 2000, Nieto et al 2000) S-phase fraction (Hellmén et al 1993) High Ki-67 proliferation indices (Zuccari et al 2004) DNA aneuploidy (Hellmén et al 1993) Number of argyrophilic nuclear organizer regions (AgNORs) (Bostock et al 1992) Higher angiogenesis (Restucci et al 2000) Tumours present for >6 months had a higher risk of lymph node metastasis (Chang et al 2005).

Non-prognostic signs • Gland involved (Schneider et al 1969) • Type of surgery (MacEwen et al 1985) • Spaying at time of treatment (some controversy but needs more study) (Chang et al 2005, Morris et al 1998, Sorenmo et al 2000, Yamagami et al 1996) • Multiple lumps (Benjamin et al 1999, Moulton et al 1986).

by the lungs. Bone, liver or brain metastases are less frequent in veterinary patients compared to human patients (Lana et al 2007).

Inflammatory carcinomas • • • •

Severe and rapid spread Red, hot, painful, pruritic Spreads laterally down legs and across midline Inoperable

Inflammatory carcinomas are rare neoplasms with an extremely poor prognosis. These tumours can often be identified at the time of presentation. Typically, physical examination reveals a firmly attached mass that is painful, erythematous and warm. It may extend to involve multiple glands and cause oedema of the peripheral limb (Figure 17.2). These patients are typically in chronic disseminated intravascular coagulation (DIC). Typically thoracic radiographs are unremarkable on presentation, but in the few patients that survive greater than 60 days pulmonary metastases will become apparent. In those cases where surgical intervention has been attempted, the complication rate was high due to the rapid recurrence and regional spread of tumour. Histology on these tumours shows significant infiltration of neoplastic cells into the lymphatics, explaining the clinical presentation of oedema. Anecdotally, radiotherapy as a palliative procedure may improve quality of life for a short period of time in certain patients but the overall prognosis for any patient with inflammatory mammary carcinoma is poor (Peña et al 2003, PérezAlenza et al 2001).

Malignant mixed tumours These arise from both the epithelial and connective tissue components of the mammary gland. They are also known as ‘carcinosarcomas’ and are relatively uncommon.

Malignant mammary tumours

Other mammary tumours

Whilst approximately 50% of canine mammary tumours are benign, between 20 and 40% are considered to be malignant and can arise from different structures within the mammary tissue (Brodey et al 1983, Gilbertson et al 1983).

• Sarcomas: These are rare tumours of the mammary gland and the origin within the mammary tissue is unknown. Sarcomas are considered to have poor prognosis. Most dogs die within 9–12 months (Hellmén et al 1993, Misdorp et al 1971).

Carcinomas Mammary carcinoma (adenocarcinoma) is the most common malignant tumour and is variously described as solid, tubular or papillary. They can be simple (epithelium alone) or complex (epithelium and myoepithelium). The infiltrative characteristics of the tumour in conjunction with the degree of invasion into local lymphatics and capillaries are important in determining the long-term prognosis regarding local recurrence and metastatic potential. The most aggressive carcinomas have lost their identifying characteristics and are described as anaplastic or poorly differentiated tumours; the latter warrant a guarded prognosis. Histological grade 0 has a 19% recurrence compared to 97% for grade II (Gilbertson et al 1983). Also similar with nuclear differentiation, poorly differentiated had 90% recurrence, 68% with moderate and 24% with well differentiated (Gilbertson et al 1983). The most common metastatic sites for mammary carcinomas are the draining lymph nodes, followed

Figure 17.2  Inflammatory carcinoma. (Reproduced from Small Animal Clinical Oncology 3rd edition, S Withrow & E G MacEwan, 2001, with permission from Elsevier.) 153

17

Tumours of the urogenital tract

• Extraskeletal osteosarcoma: These are also rare tumours and warrant a guarded prognosis due to early metastatic spread, primarily to the lungs (Kuntz et al 1998, Langenbach et al 1998) • Mast cell tumours: These should be managed as with any mast cell tumour (see Chapter 19). • Lymphoma: Lymphoma has been reported as an isolated mass in the mammary tissue as a rare occurrence.

Treatment Surgery Important features are size and invasiveness or adherence. The treatment of choice is surgical excision with appropriate margins. No clinical trial has shown improvement in survival with radical versus local removal. OHE when mammary tumours are removed does not have a significant effect on the progression of malignant disease (Morris et al 1998, Yamagami et al 1996). In another study, however, OHE at the time of mammary tumour removal improved survival 2 years after surgery, and was more beneficial for complex carcinomas than for simple carcinomas (Chang et al 2005). Sorenmo et al (2000) also found a beneficial effect of OHE at the time of mammary tumour removal. One-quarter of dogs with benign mammary tumours developed another mammary tumour within 2 years, whether they were spayed or not (Morris et al 1998). OHE helps prevent the development of further benign mammary tumours. Goal of surgery Remove the entire tumour by the simplest procedure (Figure 17.3). More surgery is not better surgery. Surgical procedures • Lumpectomy: Lumpectomy is performed for small nodules <0.5 cm that are firm and superficial. Incomplete margins are acceptable for benign lesions but if malignant, re-excision to achieve clean margins is warranted. • Mammectomy: Mammectomy to remove the whole gland is used for centrally located tumours, >1 cm, or with any degree of fixation to skin. Skin and abdominal wall fascia should be removed if involved. For malignant lesions, margins of 1–2 cm of grossly normal tissue are generally adequate. • Regional mastectomy: As above, with several glands removed together for ease of surgery (e.g. glands 1, 2 and 3 together or glands 4 and 5 together). The inguinal lymph node is usually removed en bloc with glands 4

Figure 17.3  Intraoperative mastectomy. (Courtesy S Withrow.) 154

and 5. The axillary lymph node is only removed if enlarged or cytologically positive for metastasis. • Unilateral (1–5) mastectomy: Performed to achieve multiple lumpectomies with greater ease and rapidity. It does not improve survival compared with multiple lumpectomies or mammectomies (MacEwen et al 1985). In dogs, there is minimal need for a bilateral (radical) mastectomy. There is usually also minimal loose skin to allow this to be achieved with clean margins. A better approach would be to do staged unilateral mastectomies, ensuring adequate margins are achieved with each surgery. As 50% of canine mammary tumours are benign, it is important to not perform a ‘malignant’ surgery for a benign disease. More surgery, if required, can be done later. • Bilateral (radical) mastectomy: This entails considerable morbidity, time and money and does not change survival, compared to multiple mammectomies/ lumpectomies.

Other treatments Chemotherapy For patients with aggressive mammary tumours exhibiting lymphatic or vascular invasion there is a high rate of local recurrence and metastasis. However, the role of adjuvant chemotherapy in these patients has not been adequately determined. Single-agent doxorubicin (Hahn et al 1992), doxorubicin and cyclophosphamide, and doxorubicin and docetaxel (Simon et al 2006) are chemotherapy protocols that have been used for veterinary patients with aggressive mammary carcinomas. Anecdotally, some patients are reported to have benefited from doxorubicin-based chemotherapy but prospective studies are few in number and have shown equivocal benefit from adjuvant chemotherapy. Local recurrence can be re-addressed by surgery and a second surgical procedure should be considered if the margins are not adequate. Chemotherapy should be reserved for patients at risk from metastases. Radiotherapy Radiotherapy is rarely used in the management of canine mammary cancer, but undoubtedly has a role for patients with locally recurrent disease that is not amenable to further surgery or for patients with regional metastasis to lymph nodes also not amenable to surgery. In such cases, radiation would be considered a palliative treatment. Hormonal therapy For patients diagnosed with mammary carcinoma, no benefit has been shown to carrying out OHE at the time of mastectomy (Morris et al 1998). This was to be expected due to the low levels of receptors identified on mammary tumours. In human patients anti-oestrogen drugs such as tamoxifen are effective in delaying the development of metastatic disease in those patients with oestrogen-positive tumours. No such benefit has been noted in canine patients and the oestrogenic effect of tamoxifen on the uterus resulting in pyometra or stump pyometra is an undesirable side effect. However, this drug may benefit the small number of dogs that have tumours that are oestrogen receptor positive but to establish the benefit a prospective trial would be required on suitable candidates (Morris et al 1993). At the present time there is little

Tumours of the vagina and vulva

Table 17.3  Tumours of the vagina and vulva

Figure 17.4  Uterine leiomyoma.

indication that hormonal therapy is of benefit to canine patients.

Tumours of the uterus Neoplasia of the uterus is uncommon in dogs, primarily because of the large percentage of dogs that undergo elective OHE. Most uterine tumours encountered in dogs are of mesenchymal origin (85–90% benign leiomyomas, 10% leiomyosarcomas) (Theilen & Madewell 1979). Other malignant tumours of the canine uterus sporadically reported include carcinoma (Cave et al 2002, Murakami et al 2001, PayneJohnson et al 1986, Pena et al 2006, Vos 1988).

Clinical signs Clinical signs are non-specific and these tumours may be an incidental finding. In some cases a mass can be palpated, or a vaginal discharge may be present.

Imaging Abdominal radiographs may show the presence of a soft tissue mass consistent with the uterus. Abdominal ultrasound is useful as this allows better delineation of tumour and assessment of the regional lymph nodes for evidence of metastasis.

Treatment and prognosis The treatment of choice is OHE (Figure 17.4). The value of chemotherapy or radiotherapy is unknown. In general, the prognosis for dogs with uterine tumours is good as the majority are benign.

Tumours of the vagina and vulva Tumours of the vagina and vulva are seen with greater frequency than tumours of the ovary or uterus. Most of these tumours are of mesenchymal origin (Table 17.3). Leiomyomas are typically seen in older (10–11-year-old) intact females and account for approximately 85% of all

Benign

Malignant

•  •  •  • 

•  •  •  • 

Leiomyoma Fibroma Fibroleiomyoma Lipoma

Leiomyosarcoma Adenocarcinoma Fibrosarcoma Transmissible venereal tumour (TVT)

vaginal and vulval tumours in dogs (Kydd & Burnie 1986, Thacher & Bradley 1983). Production of oestrogen is associated with growth of these tumours. The malignant variant, leiomyosarcoma, is the most common malignant tumour of the vagina and vulva. Leiomyosarcomas are locally invasive but are slow to metastasize. Other tumours reported in this region are rhabdomyosarcomas, mast cell tumours, haemangiosarcoma, squamous cell carcinoma (SCC), adenocarcinoma, epidermoid carcinoma, osteosarcoma and transmissible venereal tumours (Brodey & Roszel 1967, Herron 1983, Hill et al 2000, Suzuki et al 2006, Thacher & Bradley 1983, Theilen & Madewell 1979).

Clinical signs These are usually associated with the size and position of the mass as these tumours can be either extra- or intraluminal growths. Patients can present with a bulging of the perineum, prolapse of tumour from the vulva, dysuria, stranguria, haematuria, vulval bleeding or discharge, or tenesmus.

Physical examination An obvious swelling or protruding mass from the vulva may be visible on examination of the perineum and confirmation of location of the mass can be obtained via digital examination per rectum or per vagina.

Diagnostic work-up Routine blood work is usually unremarkable; however, anaemia, hypoproteinaemia and thrombocytopenia may occur due to chronic blood loss, and hypoglycaemia is a possible paraneoplastic syndrome. Secondary infections may also occur, causing a leucocytosis. Imaging Radiographs and ultrasound have limited application due to the intrapelvic location of these tumours. Contrast radiographic studies including positive contrast retrograde vaginourethrography are useful to determine the size and extent of the primary. Chest radiographs are indicated to rule out pulmonary metastases. Advanced imaging such as a CT scan may be beneficial.

Treatment Surgical resection is complicated by the vascularity of the vagina and vulva, and the neovascularization that occurs with tumour growth. Blood loss during surgery can be considerable. The surgeon must obtain a packed cell volume (PCV) and total protein prior to surgery, monitor for intraoperative blood loss and have an ability to provide a blood transfusion if needed. Vaginal leiomyomas and leiomyosarcomas are approached surgically via the perineum. If there is any evidence of a haem155

17

Tumours of the urogenital tract

orrhagic or purulent vaginal discharge, or the tumour is palpable via the vagina (intraluminal), the tumour is expected to involve the inner layers of the vaginal wall and an episiotomy may be needed to facilitate exposure. If the tumour is pedunculated and intraluminal, it may be removed after ligation with a transfixing suture. If it is more broad based it may be amenable to a debulking surgery or ‘shelling- out’, which is only appropriate for benign or histologically low-grade tumours. If there is no vaginal discharge, and the tumour is palpated (by a combination of rectal and vaginal examination) to be arising from the outer vaginal wall (extraluminal), an episiotomy may allow adequate visualization; alternatively, a perineal approach to the dorsal, ventral or lateral vagina may be preferable. If a preoperative incisional biopsy has shown a malignancy, e.g. an aggressive sarcoma, a squamous cell carcinoma or adenocarcinoma, a full thickness resection of the vaginal wall and tumour en bloc, followed by anastomosis of grossly normal vaginal wall (if possible) is required. The surgeon should ensure adequate exposure to confirm there is no iatrogenic damage to the urethra, and the urethra should be catheterized prior to surgery to aid intraoperative identification. An incisional biopsy should always be performed prior to extensive surgical resections to allow the surgeon to best plan surgery to obtain a potential cure. A wider resec­ tion, such as vulvovaginectomy and perineal urethrostomy (Bilbrey et al 1989), may provide a cure or improved palliation for a malignant vaginal/vulval tumour, and attempts at surgical cure ought not to be thwarted by an extensive but ‘dirty’ surgery. As leiomyomas, fibromas, polyps, leiomyosarcomas and most other vaginal tumours are hormone dependent, surgical excision of the vaginal tumour should be accompanied by OHE to prevent recurrence. The prognosis for adenocarcinoma and squamous cell carcinoma is poor due to metastasis or local recurrence, whereas benign or low-grade mesenchymal lesions have a good prognosis with treatment.

Tumours of the ovary Ovarian tumours are rare in the dog, primarily because most dogs undergo OHE at a relatively young age and, when present, are typically seen in middle to older aged dogs. Cystadenomas/carcinomas are the most common tumours encountered and account for approximately 50% of ovarian tumours (Nielsen et al 1976, Patnaik & Greenlee 1987). They can be either unilateral or bilateral. They arise from the surface epithelial layer of the ovary and malignant tumours metastasize to para-aortic lymph nodes, kidneys, omentum, liver and lungs. They will also seed tumour throughout the abdominal cavity, resulting in carcinomatosis and formation of a malignant effusion. Granulosa cell tumour develops from the gonadostromal (sex cord) tissue of the ovary. These tumours are usually unilateral and about 20% are malignant with a similar metastatic pattern as seen with cystadenocarcinomas (Hayes & Harvey 1979, Herron 1983, Neilsen et al 1976, Patnaik & Greenlee 156

1987, Theilen & Madewell 1979). Granulosa cell tumours may be hormonally active and secrete oestrogen, and comprise 50% of ovarian tumours in some reports (Dow 1960, Herron 1983, Neilsen et al 1976, Patnaik & Greenlee 1987). Other sex cord stromal tumours include the extremely rare and benign tumours thecoma and luteoma. The third category of ovarian tumours includes the germ cell tumours – dysgerminoma and teratoma/teratocarcinoma. Dysgerminomas arise from undifferentiated germ cells and are considered to be malignant in that metastasis occurs to regional lymph nodes and other abdominal organs in approximately 10–30% of cases (Andrews et al 1974, Dehner et al 1970, Neilsen et al 1976). Teratomas are usually, but not always, benign and are often composed of two or three germinal layers including bone, cartilage, brain or glandular epithelium.

Clinical signs Many tumours are incidental findings at the time of an elective OHE. However, an ovarian tumour should be suspected in any intact female with abnormal oestrus cycles. Signs consistent with excess oestrogen production may indicate the presence of a granulosa cell tumour. Presenting signs may include prolonged oestrus, alopecia, mammary hyperplasia, cystic endometrial hyperplasia/pyometra, vaginal discharge, vulval swelling, attractiveness to males and very occasionally myelosuppression due to hyperoestrogenism. Other clinical signs that may be apparent include lethargy, abdominal distension, weight loss, presence of a palpable abdominal mass and lumbar pain.

Physical examination Abdominal palpation may indicate the presence of an abdominal mass.

Diagnostic work-up In patients with chronic hyperoestrogenism there may be evidence of bone marrow suppression on haematology. This is sometimes irreversible, even with removal of the primary tumour. Imaging Plain radiographs, including thoracic films, and ultrasonography will help define the presence and location of the mass and, especially with ultrasound, the possible presence of metastases. Cytology For patients with peritoneal effusion cytology is valuable to determine the presence of malignant cells.

Treatment The treatment of choice for all patients that do not show extensive signs of metastasis is OHE. For those patients with benign tumours the prognosis is good. In patients with malignant tumours with evidence of regional spread the efficacy of chemotherapy has not been proven. Anecdotally, canine patients with carcinomatosis have responded to intracavitary cisplatin chemotherapy; however, as in humans, the effectiveness of treatment depends on overall tumour burden and patients with large intra-abdominal masses (>0.5 cm in diam-

Feline mammary tumours

eter) do not respond as well as patients with small nodules or neoplastic cells present in the effusion. Ovarian carcinoma is rare in dogs, but as in humans the potential for local dissemination throughout the abdominal cavity is high.

Feline mammary tumours Mammary tumours are the third most common neoplasm described in the cat after skin tumours and lymphoma/leukaemia (Carpenter et al 1987, Dorn et al 1968a,b, Hayes et al 1981). As with dogs, mammary tumours primarily affect female cats with an extremely low incidence in males. Also as with dogs, hormonal influences are believed to contribute to the development of mammary tumours as intact cats and cats treated with progestins have an increased risk of developing mammary tumours (approximately 10% risk of cancer with progesterone therapy). All glands are at equal risk (Anderson & Jarrett 1966, Hayden & Neilson 1971, Hayes 1977, Weijer & Hart 1983). Feline mammary tumours have been shown to express fewer steroid hormone receptors when compared to normal feline mammary tissue (Hamilton et al 1976, Hayden et al 1981). Studies have shown that cats undergoing OHE prior to 1 year of age have a significantly reduced incidence of mammary carcinoma (Overley et al 2005). Early spaying is protective but not as absolute as in the dog. Parity has not been shown to be a risk factor in the development of feline mammary tumours (Misdorp 1991, Overley et al 2005).

Figure 17.5  Pulmonary metastasis from feline mammary carcinoma. (Courtesy S Withrow.)

Signalment Most mammary tumours occur in middle-aged to older female cats, with a median age of 10–12 years. Siamese cats may be at higher risk of developing mammary tumours than other breeds and these are often bilateral (Kessler & von Bomhard 1997).

Clinical signs

Figure 17.6  Ulcerated feline mammary carcinoma. (Courtesy S Withrow.)

Table 17.4  WHO staging system for feline mammary carcinomas

Clinical signs are of a mass associated with the mammary gland that may be attached to underlying tissue or ulcerated. In some cases the tumour may be plaque-like in appearance. No other clinical signs may be apparent.

I

<1 cm

II

1–3 cm

Diagnostic work-up

III

>3 cm

As these are usually older patients, routine biochemistry, haematology and urinalysis should be carried out. Physical examination should include palpation of the regional lymph nodes. An aspirate of the nodule helps to rule out any other cause of a mammary-associated lump. Chest radiographs are indicated (left and right lateral views) to rule out metastatic lesions. In cats with metastases the typical thoracic radiograph is that of an interstitial military pattern; pleural effusion can also be present (Figure 17.5). The presence of a malignant effusion warrants a poor prognosis.

IV

Distant metastases

Malignant mammary tumours In the cat >85% of mammary tumours are malignant; the majority of these are carcinomas (Bostock 1986, Carpenter et al 1987, Hayes et al 1981) (Figure 17.6).

Stage

Tumour diameter

(With permission from the World Health Organization.)

Staging Because the majority of feline mammary tumours are malignant, staging is important and the WHO staging system for domestic animals recognizes four stages (Table 17.4). A number of studies have shown that the size of the primary at initial presentation is a good prognostic indicator and the staging system is based on tumour size (Hayes & Mooney 1985, MacEwen et al 1984, Weijer & Hart 1983). The most significant factor affecting long-term survival in cats with mammary carcinoma is tumour size. For tumours 157

17

Tumours of the urogenital tract

<2 cm, MST is >3 years, compared to 15–24 months for 2– 3 cm lesions and 4–12 months for lesions >3 cm (Ito et al 1996, MacEwen et al 1984, Viste et al 2002). Stage at the time of presentation is also prognostic, cats with stage I and early stage II disease having a longer MST (>3 years) than cats with stage II–III (MST >2 years) or late stage III–IV (MST 6 months) (MacEwen et al 1984). Extent of surgery is also prognostic, with local recurrence in two-thirds of cats with conservative resection (MacEwen et al 1984). Bilateral mastectomy resulted in an MST of 917 days, compared to 428 days for regional mastectomy and 348 days for unilateral mastectomy (Novosad et al 2006).

Treatment Surgery Radical surgery is indicated in the cat with mammary neoplasia. Unlike the dog, radical mastectomy has a better prognosis than lumpectomy, and more aggressive surgery improves overall survival (MacEwen et al 1984, Novosad et al 2006). Radical (bilateral) mastectomy and bilateral inguinal lymphadenectomy are generally performed up front at the first surgery, as cats have more loose skin than dogs, and cats are therefore more amenable to this surgery (Figure 17.7). However, if preferred by the surgeon or the client, staged unilateral mastectomies may be performed (separated by 2 weeks), as this may be less traumatic for the cat. Bilateral (radical) mastectomies create a large wound, and care should be taken to avoid hypothermia. Pain management should also be accordingly aggressive, as should postoperative supportive care. Mastectomy may be an appropriate palliative treatment, even in the cat with known metastasis, as ulcerated, bleeding, infected mammary cancers may cause significant morbidity, compared to pulmonary metastatic disease, which may be asymptomatic.

not been carried out to optimise chemotherapeutic protocols. The same combinations have been used in patients with inoperable disease where a 50% partial response rate was observed, and in those cats that did respond to chemotherapy the MST increased from 75 to 150 days. The standard dose of doxorubicin was 1.0–1.1 mg/kg every 3 weeks for five treatments. The major side effect was mild anorexia at the lower dose; increasing the dose to 1.1 mg/kg is likely to result in more profound anorexia. Myelosuppression was generally not encountered (North & Mauldin 1997). Radiotherapy Radiotherapy is rarely used in the management of feline mammary tumours but may be of some benefit in those patients with inoperable tumours.

Feline mammary hypertrophic fibroadenoma complex (Figure 17.8) This progesterone-dependent complex usually presents in young intact cats. It is induced in male and female neutered cats with exogenous progesterone. Treatment is by OHE, usually via a flank approach to avoid the enlarged mammary glands.

Chemotherapy The role of adjuvant chemotherapy, either doxorubicin alone or doxorubicin in combination with cyclophosphamide, may have some benefit in prolonging survival in patients with late stage II to stage III disease, but large prospective studies have

Figure 17.7  Bilateral mastectomy in a cat, intraoperative. (Courtesy S Withrow.) 158

Figure 17.8  Feline hypertrophic adenoma complex. (Reproduced from Small Animal Clinical Oncology 4th edition, S Withrow & D Vail, 2007, with permission from Elsevier.)

Tumours of the testicle

Tumours of the ovary Ovarian tumours are rare in the cat, accounting for only 3% of feline tumours. The reason for such a low incidence of ovarian cancer is probably related to the fact that most cats undergo OHE at a young age. The most common ovarian tumour seen in the cat is granulosa cell tumour, with clinical signs of paraneoplastic hyperoestrogenism common (Gelberg & McEntee 1985, Norris et al 1969).

Tumours of the uterus and cervix Tumours of the uterus and cervix are uncommon in the cat. The most common malignant uterine tumour in the cat is adenocarcinoma (Miller et al 2003, O’Rourke & Geib 1970). Feline uterine sarcoma has also been reported (Cooper et al 2006, Miller et al 2003, Sato et al 2007).

Tumours of the vagina and vulva These tumours are extremely rare in the cat; leiomyomas and fibromas have been reported.

TUMOURS OF THE MALE GENITAL TRACT Tumours of the testicle Tumours of the testicle are the most common tumours of the male genital tract, but as with mammary tumours in females are completely preventable by castration of male dogs not acquired for breeding purposes. One recent report found one or more testicular tumours in 27% of 232 necropsied dogs (Grieco et al 2008). Currently, these tumours account for 90% of all tumours of the male reproductive tract (Cotchin 1960, Hayes & Pendergrass 1976, von Bomhard et al 1978). They are typically seen in older male dogs, median age 10 years. Cryptorchid dogs and dogs with inguinal hernias are at higher risk of developing testicular tumours and at an earlier age. Cryptorchid testes are 14 times more likely to develop neoplasia than scrotal testes, and dogs with inguinal hernias have a five times greater risk of testicular tumours (Hayes & Pendergrass 1976). About 50% of Sertoli cell tumours and about 30% of seminomas are in cryptorchids (Reif & Brodey 1969). The three most common testicular tumours are the Sertoli cell tumour, the interstitial cell tumour (Leydig) and the seminoma, each occurring with approximately equal frequency (Cotchin 1960). It is possible to get a combination of more than one type in one dog.

Clinical signs The presence of an enlarged testicle or a mass within the testicle seen on routine examination is indicative of a testicular tumour. An abdominal mass may also be palpable, and testicular masses may be found on abdominal or testicular ultrasonography. Feminization syndrome may be the presenting clinical sign. An abdominal ultrasound is indicated to rule out a testicular tumour in any cryptorchid adult male dog.

Sertoli cell tumour (SCT) Breed predisposition has been noted in Norwegian Elkhound, Fox Terrier, Afghan Hound, West Highland White Terrier, Airedale, Weimaraner, Pekingese and Shetland Sheepdog (Cooley & Waters 2001).

Clinical signs About 50% of SCTs are found in cryptorchid testicles (Reif & Brodey 1969). SCTs can affect the ratio of oestrogen:testosterone (Mischke et al 2002). This ratio may be proportional to tumour size. The degree or presence of male feminization syndrome may depend on testicle location, with 16% of scrotal, 50% of inguinal and 70% of abdominal SCTs causing feminization syndrome (Lipowitz et al 1973). Oestrogen is bone marrow suppressive, and causes myelotoxicosis in 15% of SCTs with male feminization syndrome. Clinical signs of male feminization syndrome include nonpruritic, symmetrical alopecia (beginning in the genital and perineal region and spreading to the ventral abdomen, thorax, flanks and neck), hyperpigmentation, gynaecomastia, galactorrhoea, penile atrophy and a pendulous prepuce, attractiveness to other males and standing in a female posture to urinate, symmetrical and squamous metaplasia of prostate, and atrophy of non-neoplastic testes.

Pathology About 10–15% of SCTs are malignant (Fan & de Lorimier 2007), with metastasis to the inguinal, iliac and sub-lumbar lymph nodes as well as the lungs, liver, spleen, kidneys and pancreas. SCTs grow expansively to compress and destroy parenchyma. Oestrogen myelotoxicosis often appears as an initial transient increase in granulopoiesis and a neutrophilic leucocytosis, followed by eventual hypoplasia of all cell lines and development of pancytopenia (thrombocytopenia, anaemia, granulocytopenia) (Sanpera et al 2002).

Diagnostic work-up and staging This comprises abdominal and testicular palpation, rectal palpation, abdominal ultrasound, radiographs (abdominal and thoracic), exploratory abdominal surgery, haematology, increased plasma oestrogen, and histopathology following castration.

Treatment Castration with a wide margin of spermatic cord is the treatment of choice. For the patient with bone marrow suppression, perioperative supportive care such as fluid therapy, blood transfusions, platelet-rich plasma and broad-spectrum bactericidal antibiotics is indicated. Corticosteroids, anabolic steroids and haematinics have unknown therapeutic benefits. Haematopoietic growth factors such as granulocyte-colony stimulating factor (G-CSF) and erythropoietin may be tried.

Prognosis Complete surgical resection is curative if there is no bone marrow hypoplasia or metastasis. Mortality rate is more than 70% with severe bone marrow depression (Sherding et al 1981). Haematological parameters can take months to normalize, despite removal of the source of oestrogen. However, 159

17

Tumours of the urogenital tract

the prognosis for patients with myelotoxicity is always guarded, and persistent severe thrombocytopenia of more than 2 weeks’ duration is a poor prognostic indicator. Dogs that survive have prolonged survival (sometimes more than 1 year) (Sherding et al 1981). Haemorrhage, depression, exercise intolerance and infections may occur with persistent pancytopenia.

Interstitial cell tumour These are found in the fibrovascular stroma of the testicle. They are benign but functional. They are associated with prostatic disease and enlargement and perineal herniation (Cooley & Waters 2001). Breeds predisposed include Siberian Husky, Fox Terrier, Old English Sheepdog, Shetland Sheepdog, Bull Terrier and Dalmatian (Cooley & Waters 2001).

Clinical signs

Mixed germ cell–stromal tumours account for 7% of testicular tumours. Other less common tumours include haemangioma, granulosa cell, sarcoma, embryonal carcinoma, gonadoblastoma and lymphoma (LSA). Teratomas are very rare. Metastatic testicular tumours from gastrointestinal adenocarcinoma have been reported in three dogs (Esplin & Wilson 1998). The prognosis for most patients with testicular tumours is good. The role of chemotherapy is not well defined and has been reserved for patients with metastatic seminomas where some partial responses using platinum-based chemotherapeutic agents have been seen (Dhaliwal et al 1999). For patients with bone marrow suppression the overall prognosis is guarded due to the long period of time required for bone marrow recovery, up to 5 months (Sherding et al 1981).

Interstitial cell tumour can be an accidental finding on postmortem. Feminization is rare. There is usually a scrotal or inguinal mass. On testicular ultrasound they appear as a well-circumscribed mass with hypo- and hyperechoic areas (Johnston et al 1991).

Scrotal tumour

Treatment

Tumours of the penis and prepuce

Treatment is by castration, which is generally curative.

Seminoma Breeds predisposed include Old English Sheepdog, Siberian Husky, Fox Terrier, Norwegian Elkhound, Great Dane, Samoyed, Bulldog, Keeshond and Weimaraner. Feminization is rare (Cooley & Waters 2001).

Clinical signs Seminomas are bilateral in 18%, and 34% are found in cryptorchid testicles. Any association with prostatic disease and enlargement, circumanal gland hyperplasia, perianal tumours and perineal hernias is refuted (Cooley and Waters 2001). Metastatic rate is less than 10%. Sites include sub-lumbar lymph nodes, lungs, liver, spleen, adrenal glands, pancreas, central nervous system, eyes and skin. AgNOR counts are higher in dogs with metastatic seminoma compared to nonmetastatic seminoma (De Vico et al 1994).

The scrotum may be affected by a number of skin tumours, including mast cell tumours, SCC and haemangiosarcoma (see Chapter 20).

Tumours of the penis are rare. In certain parts of the world the most common tumour is transmissible venereal tumour (TVT); other tumours include papilloma, SCC and haemangiosarcoma. Other possible penile or preputial tumours include LSA, fibrosarcoma (FSA), histiocytic reticulocytoma, transitional cell carcinoma (TCC), chondrosarcoma (CSA), mast cell tumours (MCT) and papilloma. SCC most commonly affects the glans penis and usually presents as an ulcerated mass. It is locally invasive and can metastasize to the regional inguinal lymph node.

Clinical signs Clinical signs include haematuria or discharge from the prepuce, phimosis, increased frequency of urination or most commonly licking of the prepuce and penis due to irritation.

Physical examination

Diagnostic work-up

Extrusion of the penis usually reveals the presence of the tumour. Biopsies are recommended.

Work-up is as for Sertoli cell tumour.

Treatment

Treatment

With the exception of TVT that responds well to vincristine chemotherapy, the treatment of choice for penile tumours is surgical that may require partial or complete penile amputation and urethrostomy (scrotal or perineal). Regional lymph nodes (inguinal) should be removed if enlarged.

Treatment is by castration with a large amount of spermatic cord. Radiotherapy used in four dogs with metastatic seminoma resulted in complete remission in three dogs with no confirmed evidence of recurrence; the fourth dog died of unrelated disease (McDonald et al 1988). Platinum-based chemotherapy used in humans and cisplatin chemotherapy have been reported in four dogs with testicular tumours (Dhaliwal et al 1999). Vincristine and cyclophosphamide was not associated with a meaningful response in one dog with cutaneous metastasis (Spugnini et al 2000).

Prognosis Surgery is curative if there is no metastatic disease. 160

Other testicular tumours

Prognosis In general, prognosis is good for TVT. SCC usually carries a fair prognosis; haemangiosarcoma, due to the potential for metastasis, has a guarded prognosis.

Tumours of the prostate In general, prostatic neoplasia is seen in older dogs, mean age 10 years. Most prostatic tumours in the dog are malignant and

Tumours of the prostate

castration provides no protective effect, meaning the development of prostatic neoplasia is not strongly influenced by male sex hormones. Common canine prostate disorders include benign prostatic hyperplasia (BPH), prostatitis, cysts, squamous metaplasia, adenocarcinoma and combinations.

Clinical signs In most cases dogs will present with lower urinary tract signs of either haematuria or dysuria. In some cases the presenting problem will be for constipation or tenesmus. These clinical signs are indistinguishable from those of BPH. The clinical signs of dogs with prostate disease can be divided into four categories: • Systemic signs (fever, depression, anorexia, pain, weight loss, vomiting) • Lower urinary tract signs (constant or intermittent haemorrhagic, purulent or clear urethral discharge, recurrent urinary tract infection with dysuria, haematuria and pollakiuria, urinary retention and obstruction causing stranguria) • Abnormalities of defecation (tenesmus, ribbon stools, large bowel diarrhoea) • Locomotion disorders (stiff gait, weakness, lameness from pain).

Physical examination In some instances the prostate can be palpated as a large mass in the caudal abdomen that may be painful. Palpation of the prostrate per rectum or abdominal examination should palpate for size, shape, symmetry, mobility, pain and consistency. Normal is smooth, symmetrical, non-painful, walnutsized, with a mid-dorsal groove. Normal occupies less than 50% of the pelvic canal and is 1.1–1.3 times the length of L2 (Feeney et al 1987). Generally dogs with neoplasia, cysts and abscesses have a larger prostate, asymmetry and possibly a nodular feel to the gland; the median raphe may not be easily discernible. Abscesses are often painful to palpate. Enlarged sub-iliac lymph nodes may also be palpated. In advanced cases there may be lumbar pain associated with metastatic lesions to the lumbar vertebrae. In contrast, BPH is characterized by a uniformly enlarged and smooth prostate. Prostatic adenocarcinoma is the most common malignant tumour of the prostate; others include transitional carcinoma, squamous cell carcinoma and undifferentiated carcinoma. Less than 10% are adenomas, fibromas, leiomyomas and sarcomas. Prostatic neoplasia commonly has a great potential (70–90%) for secondary spread to pelvic lymph nodes, spine and pelvis, as well as direct spread into local tissue and distant sites (Cornell et al 2000). Pulmonary metastasis is more common in castrated dogs (Bell et al 1991). Skeletal metastasis is more common in young dogs (Cornell et al 2000).

Diagnostic work-up Routine blood work is usually unremarkable. Prostate-specific antigen (PSA) is not useful in dogs; Bell et al (1995) did not detect PSA in canine serum or seminal plasma. Serum total acid phosphatase, prostatic acid phosphatase and non-prostatic acid phosphatase were significantly higher

in dogs with prostatic carcinoma compared to normal dogs or dogs with BPH in one study (Corazza et al 1994). Bell et al (1995) found that serum and seminal acid phosphatase activities did not differ significantly between normal dogs and those with prostatic diseases, or among dogs with different prostatic disorders. Serum canine prostate specific esterase (CPSE) activities were significantly higher in dogs with BPH than in normal dogs, but dogs with BPH, bacterial prostatitis and prostatic carcinoma had similar CPSE activities. Most tumours did not stain for CPSE. Urinalysis Culture and sensitivity should always be carried out in patients with suspected prostate neoplasia. In some cases neoplastic cells will be identified in the sediment. However, the absence of neoplastic cells does not exclude the presence of neoplasia. Physical examination Rectal examination should be performed annually in an attempt to detect prostatic disease early. In the neutered dog prostatic enlargement would indicate neoplastic disease, whereas in the intact male BPH must be distinguished from neoplasia. Radiography Plain radiographs will detect prostatomegaly, but will not distinguish the various causes of the enlargement; however, calcification within the prostate seen on plain radiographs is an indication of neoplasia rather than BPH. In some instances enlargement of regional nodes or secondary lesions within the vertebrae or pelvis may be visible. Contrast studies, both negative (pneumourethrocystogram) and positive (retrograde urethrogram), will provide supportive evidence of a prostatic tumour (periurethral asymmetry as well as narrowing, distortion or destruction of the prostatic urethra). Ultrasound Ultrasonography is indicated in any presentation of prostatic disease, and has the advantage of imaging the testes, urinary tract, peri-prostatic tissue and regional lymph nodes with a combination of pre-pubic and transrectal approaches. Ultrasound can differentiate the likelihood of BPH versus neoplasia, and ultrasound-guided tru-cut biopsies can be obtained for a definitive diagnosis. The former technique is superior to prostatic washes for the diagnosis of prostatic carcinoma. Ultrasound-guided FNA is easy and has 80% correlation of cytology to histological diagnosis (Powe et al 2004). Disadvantages to ultrasound-guided biopsies are haemorrhage, damage to neurovascular supply and rectum, failure to localize the lesion and seeding infection (avoid if abscessation is suspected), as well as reports of seeding tumour (Nyland et al 2002).

Treatment Surgery Prostatic carcinomas have an 80% rate of metastasis at necropsy (Cornell et al 2000) and dogs mostly die or are euthanized due to urethral obstruction, rather than metastatic disease. Therefore, the main aim of surgery (or any treatment) is to relieve urethral obstruction with minimal morbidity. 161

17

Tumours of the urogenital tract

Aggressive surgery (prostatectomy) is mostly not recommended as the diagnosis is made too late, quality of life is not improved, and disease is not cured. In rare cases, total transurethral prostatectomy may be indicated for early stage lesions, but it is technically difficult, most dogs (93–100%) are incontinent postoperatively, and dehiscence, stenosis, infection and sepsis are common complications. Tube cystotomy (pre-pubic) and retained urethral Foley catheter are palliative surgical treatments which relieve outflow obstruction and prolong quality of life, with a well-informed and willing client. Palliative urethral stenting (placed with fluoroscopic guidance) shows great promise as a minimally invasive technique with high success for relieving outflow obstruction. When prostatic urethral stenting was carried out in eight dogs with prostate cancer, six had an excellent outcome and two had mild complications. Incontinence was mild or non-existent, and no dogs were euthanized due to urinary tract obstruction (Weisse et al 2006). Other reported minimally invasive surgical techniques such as Nd:YAG laser (L’Eplattenier et al 2006) and transurethral resection, with or without intraoperative radiation therapy (Liptak et al 2004a), have been less beneficial than stenting. Of eight dogs treated with palliative partial prostatectomy via Nd:YAG laser, three died from complications within 16 days of surgery, and the overall MST was 103 days (L’Eplattenier et al 2006). Of three dogs treated with transurethral resection and intraoperative radiation therapy, two developed urethral perforation (Liptak et al 2004a). Radiotherapy External beam radiation, either intraoperatively or as sole treatment, has limited palliative effect. Radiation therapy will shrink some tumours to relieve urinary outflow obstruction and obstipation, but survival times are short. Intraoperative radiation therapy is promising if there is localized tumour. Ten dogs treated with intraoperative radiotherapy for prostate carcinoma had a median survival time of 114 days, with a complete response in five dogs who also tolerated treatment well, two dogs ultimately died of treatment complications, and three dogs had a poor response to treatment (Turrel 1987). Chemotherapy The Cox-2 inhibitors piroxicam or meloxicam do appear to improve quality of life for individual patients although the anti-tumour effect of these drugs is questionable. In one study, dogs receiving an NSAID had an MST of about 7 months, compared to 0.7 months for those not receiving any cancer therapy (Sorenmo et al 2004). Platinum drugs Unfortunately, platinum-based protocols, with or without radiotherapy, have shown no benefit to patients with prostatic carcinoma. Mitoxantrone is the standard palliative treatment in men with hormone-refractory prostatic carcinoma, although recent studies have shown a response to docetaxel (Oudard et al 2005). Hormonal therapy No benefit can be derived for the patient from either castration or anti-androgens, as prostatic carcinomas in the dog are independent of hormonal stimulation. 162

Photodynamic therapy (PDT) PDT induced fatal prostatic necrosis (Hsi et al 2001). Another paper (Lucroy et al 2003) reported stable disease for 6 months in one dog treated with PDT.

Prognosis In one retrospective study of 76 dogs with prostatic carcinoma the MST was 0 days with 58 euthanized at diagnosis. MST for dogs living more than 7 days was 30 days (Cornell et al 2000). Survival times for treated dogs vary with the presenting clinical signs and the treatment used. The overall prognosis is guarded.

Tumours of the kidney Primary tumours of the kidney are rare in the dog and cat, approximately 1.7% and 2.5%, respectively (Crow 1985). Lymphoma is the most common tumour of the kidney in the cat (Mooney et al 1989) and carcinoma in the dog (Klein et al 1988). Other primary tumours include fibrosarcoma and haemangiosarcoma (Locke & Barber 2006). Metastatic renal tumours are more common than primary in the dog, and more than 90% of all renal tumours are malignant (Baskin & De Paoli 1977, Bryan et al 2006, Klein et al 1988). No breed predisposition has been noted in canine renal tumours, but males are more commonly affected (Klein et al 1988, Lucke & Kelly 1976). Primary tumours are usually unilateral (Bryan et al 2006), although renal lymphoma in the cat can be either unilateral or bilateral (Gabor et al 1998). Primary renal tumours other than lymphoma in cats have been reported (including carcinomas, nephroblastoma, haemangiosarcoma and adenoma) (Henry et al 1999).

Clinical signs Gross haematuria is not a consistent presenting clinical sign. Most signs are non-specific, e.g. weight loss, lethargy or anorexia (Bryan et al 2006). Other clinical signs include pain in the lumbar region, fever, abdominal distension or discomfort and pelvic limb oedema. Renal failure is rare except in cats with renal lymphoma. Early detection is recommended and any patient, particularly the older patient, presenting with haematuria should have further diagnostic tests performed immediately in the anticipation of identifying cancers at an earlier stage and improving the possibility of successful treatment. German Shepherds with renal cystadenocarcinoma may present with multiple cutaneous nodules (Lium & Moe 1985).

Diagnostic work-up Physical examination A large, painful kidney or in some cases caudal abdominal discomfort in the kidney region may be detected. Haematology and biochemistry Blood work is usually unremarkable. In some cases patients may present with polycythaemia as a paraneoplastic syndrome due to the production of erythropoietin by neo­ plastic cells (Gorse 1988, Henry et al 1999, Peterson & Zanjani 1981). A biochemistry profile should be evaluated for renal compromise and occasionally hypercalcaemia may be present as a paraneoplastic syndrome. All cats with lymphoma

Tumours of the ureter

should have their feline leukaemia virus (FeLV) and feline immunodeficiency virus (FIV) status checked. Urinalysis Proteinuria and haematuria are common findings; the presence of diagnostic neoplastic cells is rare. Imaging Plain radiographs may demonstrate renomegaly. Assessment of renal function via intravenous urography (IVU) is beneficial but in most cases evaluation of the kidneys via ultrasound is the primary diagnostic tool. Renal ultrasonography enables the architecture of the kidneys to be examined as well as assessing the patient for regional extension of the tumour, either by invasion into the vena cava or spread to local lymph nodes. MRI/CT scans are valuable when local invasion into the vena cava is suspected prior to surgical intervention. The functional status of the remaining kidney should be evaluated before nephrectomy is performed.

Treatment Surgery Unilateral disease is best treated with nephrectomy, to include ureter and retroperitoneal muscle if involved (Figure 17.9). Chemotherapy The role of chemotherapy in non-lymphoid renal tumours has not been well evaluated and, as in humans, renal carcinoma appears to be chemoresistant. For renal lymphoma, the treatment of choice is chemotherapy (see Chapter 22).

Prognosis Renal carcinoma Renal carcinoma occurs in older male, medium to large breed dogs. It can invade the caudal vena cava, and can cause paraneoplastic polycythaemia and neutrophilic leucocytosis. Metastatic disease is common in dogs, with pulmonary metastases in 16% of dogs at diagnosis and in 77% at time of death (Bryan et al 2006). The metastatic rate for cats with primary renal neoplasia (excluding lymphoma) with complete staging

was 64% and 100% for transitional cell carcinomas (Henry et al 1999). Because renal carcinomas are chemoresistant, stage and grade are important; patients with regional and distant metastase have a poor median survival time. Poor survival time reflects advanced stage, difficulty in complete excision and high metastatic rate (Klein et al 1988). Most dogs with primary renal adenocarcinoma live 6–8 months if operable (Klein et al 1988), though there have been reports of survival up to 4 years (Lucke & Kelly 1976). Bryan et al (2006) reported a median survival of 16 months for carcinomas, 9 months for sarcomas and 6 months for nephroblastomas, with surgery the only treatment. Bilateral renal cystadenocarcinoma This rare tumour is seen in German Shepherds as part of the syndrome of nodular dermatofibrosis. Slowly progressive, with metastasis in up to 43% of cases (Lium & Moe 1985), death results from renal failure, secondary skin infections and metastatic disease (Moe & Lium 1997). Nephroblastoma (Wilm’s tumour) Wilm’s tumour is the most common renal tumour in young dogs, with a mean age of 4 years, but is often seen in dogs less than 1 year of age. This embryonal tumour may be present in one pole of the affected kidney, and may demonstrate primitive epithelial and mesenchymal tissues such as vestigial tubules, muscle, cartilage and bone (White 2003). Metastasis is reported in 65% of patients and usually less than 12-month survival time when treated with nephrectomy ± chemotherapy (Coleman et al 1970, Frimberger et al 1995), with one report of survival more than 25 months (Seaman & Patton 2003). However, nephrectomy may ensure prolonged survival or cure in some cases (Seibold & Hoerlein 1957, Simpson et al 1992). Benign renal tumours Except for haemangioma, these are usually asymptomatic, e.g. fibroma, myxoma, lipoma, mixed tumours, leiomyoma, adenoma and papilloma. Renal lymphoma Stage, degree of response, FeLV status and renal function are prognostic factors for cats with renal lymphoma. MST is 408 days if complete response is achieved, 75 days with partial response, 267 days if FeLV positive and 610 days if FeLV negative (Mooney et al 1989). Patients with azotaemia that does not resolve after induction chemotherapy have a poor prognosis (see Chapter 22). Renal lymphoma is rare in the dog. Mesenchymal renal tumours These tumours have an MST of 9 months postsurgical excision (Bryan et al 2006). Renal haemangiosarcoma is a rare anatomical variant of haemangiosarcoma with improved survival times over splenic disease (Locke & Barber 2006).

Tumours of the ureter

Figure 17.9  Renal carcinoma (sectioned). (Courtesy R Straw.)

Primary tumours of the ureter are extremely rare in both the cat and the dog and are typically leiomyoma/sarcoma or transitional cell carcinomas. The ureters can be involved due to invasion by either renal or bladder tumours. Obstruction of the ureter with tumour leads to the development of hydroureter 163

17

Tumours of the urogenital tract

and hydronephrosis in the affected kidney; however, providing only one ureter is affected, signs of renal failure may not be apparent and signs similar to obstruction due to urolithiasis may be seen, i.e. lethargy, lower back pain, anorexia.

2000, Mutsaers et al 2003, Norris et al 1992). Breeds overrepresented include West Highland White Terrier, Jack Russell Terrier, Beagle and Scottish Terrier (Sapierzyn´ski et al 2007).

Diagnostic work-up

The most common presenting clinical sign is haematuria that may be temporarily responsive to antibiotics. Other clinical signs seen are consistent with lower urinary tract signs including stranguria and dysuria. In extreme cases patients may present with anuria due to complete obstruction of the urethra with tumour. In some cases patients may present in renal failure due to obstruction of the ureters at the level of the trigone. It is imperative that older patients with haematuria receive an appropriate work-up rather than being kept on antibiotics as unfortunately delay in diagnosis often means that these tumours are diagnosed only when they are extremely advanced. High concentrations of basic fibroblast growth factor have been found in the urine of dogs with cancer and the hope is that such assays may lead to earlier detection of bladder cancer (Allen et al 1996).

An IVU will allow precise evaluation of a ureteral neoplasm in conjunction with abdominal ultrasound to evaluate the ipsilateral kidney.

Treatment The treatment of choice is ureteronephrectomy. The functional status of the contralateral kidney should be evaluated prior to surgery. These tumours are rare and no chemotherapy protocols have been described.

Prognosis The prognosis is guarded for malignant tumours; however, leiomyosarcomas are slow to metastasize and therefore excision would carry a fair prognosis. The worst prognosis would be expected for TCC of the ureter because of its higher metastatic potential.

Tumours of the urinary bladder

Clinical signs

Staging Staging of bladder tumours is according to the TNM system (Table 17.6).

The urinary bladder is the most common location of canine urinary tract tumours, and accounts for approximately 1% of all canine neoplasms (Crow 1985, Mutsaers et al 2003). The most common tumour is transitional cell carcinoma, which accounts for approximately 90% of canine bladder tumours (Norris et al 1992, Rocha et al 2000, Valli et al 1995). Other malignant tumours seen in the urinary bladder include adenocarcinoma, sarcomas, haemangiosarcomas and lymphomas (Benigni et al 2006, Liptak et al 2004b, Norris et al 1992, Olausson et al 2005, Rocha et al 2000, Valli et al 1995). Benign tumours include polyps (Martinez et al 2003) and leiomyomas (Heng et al 2006) (see Table 17.5).

Transitional cell carcinoma (TCC) TCC is typically invasive and is most often located in the trigone region of the bladder (Figure 17.10). These tumours are malignant and will metastasize to the local lymph nodes and lungs, with about 30% of patients having metastases at the time of diagnosis (Knapp et al 2000).

Figure 17.10  Bladder transitional cell carcinoma.

Signalment TCC is found typically in middle-aged to older dogs, with an overall incidence greater in females than males (Knapp et al

164

Table 17.6  TNM classification of canine bladder tumours

Table 17.5  Tumours of the canine urinary bladder

Tumour

Node

Metastasis

Benign

Malignant

T0: no evidence of tumour

N0: no nodal involvement

M0: no distant metastasis

•  Leiomyoma •  Fibroma •  Haemangioma

•  •  •  •  •  •  •  • 

T1: superficial tumour

N1: regional node involvement

M1: metastasis present

T2: invading bladder wall

N2: regional and juxtaregional node involvement

Transitional cell carcinoma Adenocarcinoma Leiomyosarcoma Haemangiosarcoma Lymphoma Squamous cell carcinoma Rhabdomyosarcoma (embryonal) Fibrosarcoma

T3: tumour invading regional organs

Tumours of the urethra

Diagnostic work-up Bladder tumours are most routinely diagnosed via ultrasound and ultrasound-guided biopsies have a sensitivity and specificity of 90%. Ultrasound-guided or blind catheter biopsies are also useful, and avoid the complication of tumour seeding, although care must be taken not to rupture the urethra or bladder neck (Holt et al 1986, Lamb et al 1996). Cystoscopy, when available, has a specificity and sensitivity of close to 100%. Contrast studies are valuable to delineate any intraluminal mass. Care should be taken when aspirating any bladder mass as TCC is known for ‘seeding’ along the needle tract (Nyland et al 2002, Vignoli et al 2007). TCC usually arises in the trigone area of the bladder so the ureters and kidneys should be evaluated for hydroureter and/ or hydronephrosis.

Treatment Surgery Partial cystectomy alone has been reported to result in an MST of 3–6 months. Stone et al (1996) reported 11 dogs with bladder neoplasia treated by partial cystectomy, with 5 dogs euthanized 2–7 months after surgery, 6 dogs surviving at least 1 year and 2 of these alive at 17 and 27 months. In general, tumour-free margins are impossible (Knapp et al 2000). Failure is attributable to local recurrence due to the seeding of tumour throughout the urinary bladder and both regional and distant metastasis. Chemotherapy In humans with TCC the platinum-based drugs have been used with good success rates. However, in humans, early detection and more superficial disease result in better outcomes than in veterinary patients. Approximately 20% of human patients have invasive TCC and do not respond well to platinum-based chemotherapy; unfortunately, dogs with TCC have tumours similar to this small percentage of human patients. A number of studies have evaluated the efficacy of chemotherapy in dogs with non-resectable TCC. The response rate for patients treated with cisplatin was <30% (Chun et al 1996) and the potential nephrotoxicity has meant that cisplatin is not currently recommended. The cisplatin analogue carboplatin has been examined as an alternative to cisplatin. Unfortunately, the response rates were poor, with one study reporting no survival benefit from carboplatin chemotherapy when used as sole agent (Chun et al 1997). The cyclooxygenase inhibitor piroxicam (Feldene) was shown in a number of studies to improve quality of life for patients with TCC. The main side effects included gastrointestinal irritation and sub-clinical renal toxicity. At the recommended dose (0.3 mg/kg once daily) the median survival time was 181 days (Knapp et al 1994). Clients report an improvement in clinical signs with an improved quality of life for these patients. The combination of cisplatin and piroxicam resulted in clinical nephrotoxicity and is not recommended for the treatment of TCC (Chun et al 1996, Mohammed et al 2003). Carboplatin and piroxicam resulted in remission in about 40% of patients with median survival of 161 days (Boria et al 2005). Mitoxantrone, a drug related to doxorubicin, has been

combined with piroxicam and in one study the overall survival time was increased from 181 days with piroxicam alone to 291 days on combination therapy in 48 dogs (Henry et al 2003). The protocol consisted of four cycles of mitoxantrone (5 mg/m2 intravenously) at intervals of 3 weeks, with piroxicam administered at the standard dose throughout. In general, the protocol was well tolerated with subjective improvement in 75% of the treated dogs. Diarrhoea and azotaemia were the most common side effects. Currently, for dogs with non-resectable TCC, the combination of mitoxantrone and piroxicam, and piroxicam alone, are the primary treatment options. Meloxicam has also been shown to have a similar effect on bladder tumours as piroxicam and is often substituted for it. Radiotherapy Radiotherapy intraoperatively, either as a single treatment or as part of a fractionated programme, has been shown to give good long-term local control; however, the side effects of treatment – primarily bladder fibrosis and urinary incontinence – have meant that this treatment modality is rarely carried out in veterinary medicine. Cisplatin in combination with radiotherapy did not show any advanced survival over radiotherapy alone (Walker & Breider 1987).

Tumours of the urethra Neoplasia of the urethra is uncommon in both the dog and cat. In the female dog the major differential is granulomatous urethritis. Urethral neoplasia is seen most commonly in the older female, with no known breed predisposition. TCC is the most common tumour of the proximal third of the urethra, and squamous cell carcinoma the distal portion of the urethra and urethral tubercle. These tumours are invasive and will metastasize to local lymph nodes and pelvic organs. Very rarely sarcomas of the urethra will be seen (Figure 17.11). Granulomatous urethritis is an important differential diagnosis. Multiple chondrosarcomas in the urethra of a dog have been reported (Davis & Holt 2003). In 20 cases of canine primary urethral neoplasia, SCC was the most common. The most useful diagnostic method was pneumocystography-cystography, with voiding urethrography. Metastasis occurred in 6 of the 20 dogs (Tarvin et al 1978).

Clinical signs These are consistent with lower urinary tract signs, i.e. dysuria, pollakiuria, haematuria and stranguria.

Physical examination Many of these tumours are palpable, either on rectal or vaginal examination. They may be palpated as either a discrete mass or diffuse swelling of the urethra.

Diagnostic work-up Endoscopy and positive contrast studies are the most useful diagnostic procedure. Surgical exploration and treatment may be necessary if imaging is not helpful. Abdominal ultrasound and thoracic radiographs are performed prior to extensive surgery for staging purposes. 165

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Tumours of the urogenital tract Figure 17.11  Contrast study in a dog with a urethral sarcoma.

Treatment Surgery An incisional biopsy is important to rule out granulomatous urethritis before extensive surgery or euthanasia. Incisional biopsies may be obtained surgically or using endoscopic biopsy forceps. For definitive surgery, a combination of perineal, pelvic or abdominal surgical approaches may be required, depending on tumour location. Contrast radiographic studies are useful to help plan the surgical approach. Urinary diversion techniques may be required if the urethra cannot be reconstructed. Urethral stenting may be useful for nonresectable tumours, e.g. TCC. Chemotherapy TCC of the urethra responds as for bladder TCC.

Feline urinary tumours Bladder tumours Bladder tumours in cats are rarely reported, but seem to be different from those in dogs in that only 15 of 27 cases reported were carcinomas, the remainder were mesenchymal (leiomyoma, leiomyosarcoma and haemangiosarcoma) or lymphoma. Four of nine cats treated with partial cystectomy had mesenchymal tumours, and lived >6 months after surgery (Schwarz & Willer 1989).

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